Division of Neuroscience, Departments of Medicine and Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA, United States.
Departments of Preventative and Restorative Dental Sciences and Oral and Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA, United States.
Pain. 2021 Mar 1;162(3):907-918. doi: 10.1097/j.pain.0000000000002073.
Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.
虽然临床研究支持压力是导致化疗引起的周围神经痛（CIPN）的危险因素的观点，但几乎没有科学证据支持这种联系。在这里，我们评估了压力对雄性和雌性大鼠奥沙利铂诱导的 CIPN 的影响及其潜在机制。单次奥沙利铂给药在两性中均产生相似程度的机械性痛觉过敏，在第 28 天仍保持相似程度。肾上腺切除术减轻了两性奥沙利铂诱导的痛觉过敏。为了确认神经内分泌应激轴在 CIPN 中的作用，鞘内给予靶向β₂-肾上腺素能受体 mRNA 的反义寡核苷酸，仅在雄性中预防和逆转了奥沙利铂诱导的痛觉过敏。相比之下，糖皮质激素受体反义寡核苷酸在两性中预防和逆转了奥沙利铂诱导的痛觉过敏。不可预测的声音应激增强了两性的 CIPN。应激激素肾上腺素、皮质酮及其组合在应激水平下的给药，模拟了声音应激对 CIPN 的影响，仅在雄性中。在雌性中，只有皮质酮模拟了声音应激的作用。此外，还评估了 CIPN 的一个风险因素，即早期生活应激，通过在成年期产生应激敏感（由新生儿有限的床上用品产生）和应激耐受（由新生儿处理产生）表型来实现。尽管新生儿有限的床上用品显著增强了雌性成年期的 CIPN，但新生儿处理显著减轻了两性的 CIPN。我们的研究表明，2 种主要神经内分泌应激轴在奥沙利铂诱导的神经病理性疼痛中具有性别二态作用。
